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Over the past few decades, the pharmaceutical industry has experienced tremendous growth on a global scale. Assuring the quality of the packaging is of utmost importance to every manufacturer since any defect in the packaging of pharmaceuticals can have major consequences. Pharmaceutical products must be free from microbiological contamination and safe to use from the time of manufacturing until the end of their shelf life. Through contamination in the form of oxygen, humidity, or microbial entry, the stability of the drug may be negatively impacted. Container closure integrity tests with great sensitivity are needed to reduce these risks. Hence, manufacturers choose helium leak detection technology.

Overview of SIMS 1915+

Helium Leak Detection using Seal Integrity Monitoring System (SIMS) 1915+ is a highly sensitive test method for inspecting the integrity of pharmaceuticals to identify leaks. Helium as a tracer gas may be used to quantitatively evaluate packages, providing higher degrees of accuracy than conventional vacuum bubble and dye penetration test methods. This approach makes it possible to compare various package types, sizes, and configurations, as well as manufacturing line settings and storage conditions, throughout the lifespan. LDA SIMS 1915+ is a tried-and-true technique that can be used for a range of package types, including cold form blister cards, foil pouches, parenteral vials, syringes, bottles, pre-filled syringes, and other unique medical devices. It can also be used for package design, tooling qualification, production line setup, and ongoing product quality monitoring.

SIMS 1915+ Low Temperature Add-on Test Systems

In an effort to maintain product quality aspects, complex pharmaceutical and biologic compositions have led to a constant drive towards deeper cold storage. These products, which are frequently protein-based or cell or gene treatments, must be stored in conditions that may include dry ice (-78.5°C) or even liquid nitrogen (-200°C) for storage and delivery.

The packaging system such as screw or crimp cap vials in which the products are enclosed is frequently quite conventional in nature, even if the products necessitating such deep cold storage may be complex. At these temperatures, many of the materials employed in these package systems and responsible for preserving package integrity are not normally evaluated. When subjected to deep-cold or ultra-cold temperatures, elastomeric components in particular may undergo physical changes when materials reach or exceed their glass transition state, resulting in leaks at low temperatures that would not normally be visible at room temperature. This type of leakage is frequently seen in primary seal regions, such as the interface between an elastomeric closure and a glass vial, when the temperature is below -60°C. In order to minimize leakage and demonstrate a deep understanding of a package system's performance in accordance with USP 1207, manufacturers need a method for evaluating container closure integrity while at these low temperatures. This significantly led them to decide on the best package choice and design as well as assembly parameters.

PTI and LDA’s engineering team developed the LT80, or Low Temperature -80°C, Test System, for use with the SIMS range of helium leak detectors to satisfy the market need for analyzing fine leakage at low temperatures. The LT80 system, which incorporates an SP Corporation Chiller, enables simultaneous temperature conditioning, temperature monitoring, and helium leak testing of packages down to -80°C. LT80 combines the recently announced features of the market-leading, Agilent Technologies-based SIMS 1915+ with 21 CFR Part 11 compliant SIMS Software. This is available as an upgrade for current SIMS units in the field or as a complete system. The SIMS 1915+ LT80 package is the first helium leak testing equipment particularly designed for low temperature testing down to -80°C. Sample testing close to -150°C is possible with the LT150 add-on low temperature unit.

LDA (a PTI Company) is the leading global producer of specially designed leak detection systems for pharmaceuticals and medical equipment. LDA’s low temperature add-on systems are ideal for evaluating fine leakage at cold temperatures using Helium Leak Detection Technology.

Combination products, which provide effective and novel treatment options and approaches across various disease states, have made a significant influence on the healthcare landscape in recent years. The acceleration of growth in this field of science and medicine is expected to continue propelling at an increased rate. The packaging and device industry has focused its innovation specifically on combination therapeutics to fulfill the demands of both drug developers and patients. To ensure that the best results may be obtained, these therapeutic products need to be tested for integrity and quality using a very sophisticated approach.

Challenges Faced by Combination Products

Patient safety can be improved by addressing these three challenges.

• Device Robustness and Reliability

If a pharmaceutical or biologic is not administered safely, properly, and consistently, it cannot benefit the patient. The delivery method for this is a sturdy, dependable device, and the technique to make sure that the device performs as intended is through the design control process. Verification testing is an important stage that ensures the device has been developed appropriately and operates dependably in accordance with established patient needs and drug specifications. Additionally, it assesses how well the product will withstand in the most adverse circumstances, which may include drops, climatic extremes, and moisture exposure.

• Drug - device integration

When developing combination products, it's crucial to take the interaction between the device and the drug into consideration. The FDA categorizes combination products into nine separate categories, which include pre-filled drug devices or delivery systems as well as devices that have been coated, impregnated, or mixed with drugs or biologics. The development process can be considerably influenced by the precise combination of components as well as the crucial interfaces.

• Accommodating various volumes

Large drug volumes have been difficult for patients to self-administer using devices like autoinjectors, pens, or pre-filled syringes. But the development of wearable devices is changing the game by enabling greater volumes to be administered subcutaneously over a longer period. This increases the potential for patient-centered healthcare but poses a number of manufacturing and packaging challenges.

Here, we will discuss how helium leak testing helps in testing the combination products.

Testing Integrity of Combination Products Using Helium Leak Testing

Helium leak detection is a highly sensitive technology for identifying leaks in any closed or sealed system using helium gas and monitoring the concentration of the gas as it escapes due to a leak. The integrity of a variety of complicated pharmaceutical and parenteral products may be evaluated using helium leak detection. Combination products, cold form blister packs, foil pouches, pre-filled syringes, and many more drug packages can be tested using helium leak testing. This technique is the best option for verifying the integrity of pharmaceutical products since it can accurately determine integrity between certain major container closure system components.

Helium leak detection works as follows: The package is initially vacuumed and helium filled. The quantity of helium leaving the package is then measured quantitatively and expressed as a leak rate using a helium leak detector. Helium leak testing is used in product design, product quality evaluations, failure analyses, and validation in addition to examining the integrity of container closures. It is possible to test "in-leakage" or "out-leakage" as well as the location of leaks using helium leak testing, which may be employed with or without a test chamber.

Helium Leak Testing Applications

• Seal integrity monitoring during stability studies.
• Useful in the early stages of developing a drug product packaging system.
• Selecting closure formulation and configuration.
• Ensuring container closure integrity.
• Verify and predict shelf-life seal integrity.

The need for complex drug delivery systems and combination products continues to fuel the development of new products and innovation within the medical device industry. At LDA (a PTI Company), we understand that the combination of medical devices and pharmaceuticals opens a world of promising new opportunities. LDA has the experience and expertise necessary to seize these opportunities and assist clients in testing combination products.

Container closure integrity is essential for patient safety as well as pharmaceutical product efficacy, and container closure integrity testing (CCIT) is a critical step in the manufacturing process. A paradigm change is currently taking place in the pharmaceutical industry, moving it away from conventional probabilistic procedures and toward deterministic alternatives. LDA (a PTI Company) dives into the area of CCIT, giving the industry a thorough understanding of its practices and introducing innovative helium leak detection technology.

For non-porous packaging including vials, syringes, and cartridges, helium mass spectrometry has become the new leak detection standard. The approach is favored by producers and authorities because of its greater sensitivity, quicker test times, traceability, and determinism in contrast to the probabilistic conventional methods.

Role of Helium Mass Spectrometry in Leak Testing Vials

Helium mass spectrometry is a leak detection standard for various pharmaceutical packaging formats, including vials. Mass spectrometer leak detector is an equipment often used for discovering and identifying leaks within or outside the product. Typically, it works with a vacuum chamber and a closed container filled with helium. Helium leakage from the container is measured by the mass spectrometer. In this technique, the product connected to the detector is filled with helium tracer gas. Helium from the tested product escapes into the detector, where it is measured and indicated as partial pressure.

The sector field mass spectrometer works as the fundamental component of leak detection. Helium gases are ionized as they enter the vacuum. Next, voltage is added to accelerate the helium ions, which are subsequently separated in a magnetic field. A specific detector is used to change the ion current into an electric current. Utilizing leak detecting units, this current is accelerated and displayed on the screen. The leak will be determined by the current since it is directly proportional to the helium concentration.

Why is Helium Used in Leak Detection?

• It is an inert gas molecule that is among the smallest.
• It may consistently and readily breach pathways due to its small atomic size.
• Helium is non-toxic, non-condensable, and non-flammable.
• Relatively safe to use as it will not interact with the components being tested.
• Helium is less expensive and readily available when compared to other tracer gases.
• There is no more than 5 ppm of helium in the atmosphere.

For Maximum Allowable Leakage Limit (MALL) testing in the pharmaceutical industry, LDA helium leak detection technologies are ideal. It is crucial that you control the tracer gas concentration while doing the measurement to guarantee accuracy. This is particularly challenging when working with vials or other sealed containers. Therefore, LDA (a PTI company) provides solutions to test the integrity of pharmaceutical vials.

Do you rely only on the traditional blue dye leak test method to ensure the integrity of blister packaging? While background knowledge of preventing blister pack leaks is recommended, package integrity testing is necessary.

Pharmaceutical package leak detection ensures that the product remains safe and effective in the packaging while maintaining sterility. A proper sterile container prevents air penetration and maintains product safety and effectiveness. Ingress of air from blister pack leaks, such as micro leaks and pinholes, may have a severe negative impact on pharmaceuticals, therefore you must be completely confident in your pharmaceutical package integrity, ensuring it passes the required integrity test. The best way to ensure that the pharmaceutical packaging has no significant blister pack leaks is with the helium leak detection method.

SIMS 1915+ for Blister Pack Leak Testing

Seal Integrity Monitoring System (SIMS) 1915+ helium leak detection is an ideal solution for testing the integrity of cold form blister packs. The packages may be quantitatively evaluated using helium as the tracer gas, which provides more precision than typical vacuum bubble and dye penetration test processes. This approach allows for the lifetime comparison of various packing materials and forms, as well as production line settings and stable storage conditions. LDA SIMS 1915+ is a tried-and-true method for a wide range of package types, including foil pouches, parenteral vials, syringes, bottles, pre-filled syringes, and unique medical devices. It can be used for package design, tooling qualification, production line setup, and ongoing product quality monitoring.

Each SIMS 1915+ helium leak testing equipment is built to the customer's specifications. It is composed of an oil-free pump, detector, and integrated power system that enables quantitative analysis of package systems at sensitivity levels as low as 1 x 10 -10 mbar L/s at room temperature. The most basic component is the Helium Leak Detector Module (HLDM), which is built within a Console Frame Assembly that includes a Stainless Steel working surface and an optional Dual Test Port Manifold. The freestanding consoles are easy to use and relocate since they include a locking wheel and an articulating arm mechanism for attaching the computer and accessories.

Helium Leak Detection SIMS 1915+ Configurations for CCI

• Helium Leak Detector Module (HLDM): Oil-Free, Production version in Console Frame Assembly, with Stainless Steel working surface and Nitrogen Vent Supply System for the Helium Leak Detector Module.
• Vacuum Test Fixture Model (VTFM): a custom-made fixture for testing vial container samples.
• Model VM-2 Head Space Analyzer Module (HSAM): includes three (3) Puncture Probes (two spares) for determining Helium Concentration in the headspace of vial containers.
• Dual Test Port Manifold that allows concurrent use of VTFM & HSAM on HLDM unit.
• An integral Calibration Chamber (with Calibrant Gas Flow Meter/Controller) for HSAM Calibration and a Universal Holder for various vial sizes are offered.
• Helium Leak Standard Calibrated Externally for System Calibration/Validation.

Blister Packs are intended to protect the contents from both internal leakage and contamination from outside sources. Helium leak testing is a CCI test method used to locate and measure leaks in medical and pharmaceutical packaging to ensure package and seal integrity. The package can be tested alone or with the contents inside. With over 25 years of expertise in the pharmaceutical packaging industry, LDA (a PTI Company) is continually looking ahead to enhance blister pack leak detection.

USP <1207> Package Integrity Evaluation of Sterile Products provides an overview of relevant and authorized test procedures that may be utilized to achieve certification criteria. Developing a basic knowledge of these methodologies will allow you to make an informed decision on the most effective test methodology for a specific container and package system. Various CCI test methods are available today. Among them, helium leak testing has proven to be the most chosen method due to its extreme test sensitivity.

Why Use SIMS 1915+ for Leak Detection?

Seal Integrity Monitoring System (SIMS) 1915+ is the perfect choice for a helium-based leak detection system. Using helium as the tracer gas, packages may be quantitatively analyzed to levels much above the vacuum bubble and dye penetration test processes. This quantitative technique supports the entire lifetime by providing direct comparison across numerous packing materials and types, production line settings, and stable storage conditions. SIMS 1915+ can be used for package design, tooling qualification, manufacturing line setup, and continuous product quality monitoring. Each SIMS 1915+ helium leak testing equipment is built to the customer's specifications. SIMS 1915+ can do quantitative CCI analyses on packages with sensitivity as low as 1 x 10 -10 mbar L/s.

What are the Applications of SIMS 1915+?

• Vials

Vials composed of glass and polymer are the most widely used package systems tested using helium leak detection. Vials are provided with a variety of capping to fulfill specific storage or handling needs. Vials are commonly used to store drugs or laboratory samples. Micro leaks in vials that carry sensitive drugs cannot be detected with a visual inspection. Helium leak testing is an ideal method for component qualification for empty components as well as a product-filled vial.

• Pre-filled syringes

The use of pre-filled syringes has increased significantly in the pharmaceutical industry. CCI analyses of pre-filled syringes are more complicated, but they are much more important in ensuring entire system integrity. Helium leak testing for leak detection of pre-filled syringes has proven to be an effective method for evaluating the CCI of pre-filled syringes.

• Bottles

Bottles made of glass or plastic are cost-effective traditional dosage forms ideal for the oral administration of syrups, solutions, and suspensions. Helium leak testing offered by LDA, a PTI company, quickly and effectively tests bottles for leaks and thereby defective bottles can be removed from the production line easily.

• Blister packs

Due to the extreme sensitivity offered, the helium-based test method for evaluating the integrity of a blister card containing solid dose pharmaceutical drugs has been proven to be the most effective approach. Helium remains an ideal test method for qualifying the material components of CFF blister cards.

• Foil pouches

Pharma manufacturers typically use foil pouches when a drug product requires multi-layered packaging. Helium leak testing of foil pouches is a viable and highly sensitive approach to meet strict regulatory requirements.

• Combination products

These are multi-chamber systems that require unique test requirements. Helium Leak Detection as per ASTM F2391 is a well-established and widely used method for testing combination products. Testing combination products using helium leak testing ensure all components meet the strict leak rate requirements.

LDA’s (a PTI company) Seal Integrity Monitoring System (SIMS) 1915+ is an efficient method for a wide range of package types such as pre-filled syringes, cold form blister cards, foil pouches, parenteral vials, and unique medical devices. Seal Integrity Monitoring System (SIMS) Model 1915+ Helium Based Leak Testing System is designed specifically for the needs of the pharmaceutical and medical device industries.

With the rapid growth of the cell and gene therapy sector, there is a higher demand than ever to prove Container Closure Integrity (CCI) at low temperatures. Most cell and gene therapy drugs are maintained at temperatures below -60°C to preserve the effectiveness of the product. Many of these items are packed in vials or cryogenic freezing bags. Vials made of glass or plastic are the most commonly used containers for packing. They are used to preserve pharmaceuticals or laboratory samples. Each of these container closure systems presents a unique challenge for determining CCI at low temperatures. In this blog, we will discuss how the integrity of vials can be tested using low-temperature package test systems.

Low-Temperature Test Systems for Vial Integrity Testing

The most common challenge in storing vial systems at ultra-low temperatures is the occurrence of transient leaks. While a vial system may achieve leak rates at or below the maximum permissible leakage limit (MALL) at room temperature, the same may not necessarily be true at -80°C or lower. However, many of the materials used in these package systems and those responsible for maintaining the integrity of the package are not normally evaluated at these temperatures. Physical changes can occur, especially in elastomeric elements, when in contact with deep-cold or ultra-cold temperatures, causing the material to reach its glass transition state or higher. This results in leakage at low temperatures, which is not observed at room temperature. This type of leakage is most commonly found in primary sealing areas between elastomeric closures and glass vial, such as below -60°C. Having a reliable method to test container closure integrity while at these low temperatures enables manufacturers to minimize leakage.

LDA has developed the LT80, low temperature -80°C add-on test system for use with LDA SIMS helium leak detector to meet market demand for cold temperature leak analysis. Concurrent temperature conditioning, temperature monitoring and helium leak testing of packages approaching -80°C are all possible on the LT80 system. Helium leak detection is an effective way to ensure container closure integrity, even at temperatures below -80°C. Although there are alternative methods for measuring CCI, many of them are ineffective at temperatures below -80°C. LT150 low-temperature add-on unit allows sample testing at temperatures as low as -150°C.

Applications of Helium Leak Detection

• Ensuring container closure integrity.
• Seal integrity monitoring during stability studies.
• Verify and predict shelf-life seal integrity.
• Useful in the early stages of developing a drug product packaging system.
• Selecting closure formulation and configuration.

Helium leak detection is a rapid, efficient, and deterministic method of determining the inherent CCI of a vial system at any temperature. Due to the sensitivity of helium leak detection, it is excellent for testing CCI for products that must retain both headspace gas and sterility. During the package development phase of the product life cycle, helium leak detection is most commonly utilized in evaluating component performance at ultra-low temperatures.

Pharmaceutical bottle integrity testing is an important step in assuring that the product is safe and unadulterated. It analyzes the strength and integrity of the closure mechanism as well as its capacity to maintain a sterile barrier. Container closure integrity testing analyzes the materials and chemicals for the possibility of migration or leaching into the drug product, resulting in contamination. Microorganisms, gases, and other chemicals are examples of contaminants. Container system integrity testing involves evaluating primary packaging, or everything that comes into direct touch with the product, as well as secondary packaging components required for package assembly. Helium leak detection, airborne ultrasound, vacuum decay, and high voltage leak detection are all methods for verifying the safety of container closures.

Helium Leak Detection to Ensure the Integrity of Bottles

Helium leak detection is referred to as a method of finding leaks in a sealed or enclosed system using the helium tracer gas method. The amount of helium that leaks through a breach is measured and is stated as a leak rate. It is an effective container closure integrity test technique for determining the integrity of pharmaceutical and parenteral products. Helium leak testing guarantees the sterility of drug substances and drug products packaged and, therefore, enhances patient safety.

In this method, the package is filled with helium and subjected to vacuum. The quantity of helium that exits the package is measured using a helium leak detector. The result is expressed as the leak rate. Helium leak testing, in addition to being a highly sensitive container closure integrity test technique, is also useful in product design, product quality analyses, failure analysis, and validation.

What are the Applications of Helium Leak Testing?

Some of the most important applications of helium leak testing include:

• Ensuring container closure integrity.
• Selecting closure formulation and configuration.
• Seal integrity monitoring during stability studies.
• Verification and prediction of shelf-life seal integrity.
• Useful in the early stages of developing a pharmaceutical product packaging system.

Helium leak detection offered by LDA (a PTI company) is one of the commonly used leak testing methods that can be used for pharmaceutical package leak detection. Bottles can be tested very effectively using this method. The applications of helium leak detection are also found in vials, prefilled syringes, foil pouches, and cold form blister cards. LDA has long-time expertise in designing leak testing equipment for pharmaceuticals and medical devices.

Foil pouches are a simple solution for sterile barrier packaging. These are ideal for medical equipment and pharmaceuticals as well. Aluminum foil, which is impermeable to moisture, oxygen, and other gases, as well as microorganisms and light, helps to preserve pharmaceuticals in perfect condition for a longer period of time. These materials are used to create films that are free of contaminants and toxins. As a result, one advantage of foil pouches is that they may be used to package both food and non-food products. Another benefit of utilizing foil pouches is their low cost. Foil pouches are less expensive than many packaging materials.

Leak testing foil pouches is a challenging process. Leaking pouches may destroy the quality of the product by destroying the outside package. More significantly, leaking pouches provide a point of entry for contamination into the product, which can result in product degradation and potential health risks for patients. This creates the necessity of testing foil pouches and helps assure package quality.

How Helium Mass Spectrometer Detect Leaks in Foil Pouches?

Helium leak testing is a CCI testing method for leak testing foil pouches. It is the process of finding leaks in an enclosed system using helium as the tracer gas. Helium leak testing is one of the most accurate and rapid leak detection methods which employ a mass spectrometer for analyzing/measuring leaks. For a variety of reasons, helium gas is used to locate leaks. These include the fact that it is present only 5 ppm in air, resulting in very low background levels. Helium has a low mass and is completely inert/non-reactive. Helium is also non-flammable, abundantly available, and inexpensive.

Helium mass spectrometer is a device that helps in detecting and locating leaks. The device being tested is either pressurized from the inside or pressurized with helium from the outside. The gas from any possible leaks is collected and pumped into the mass spectrometer for analysis, and any value over the helium background trace indicates a leak. The mass spectrometer works as follows-any helium molecules vacuumed into the spectrometer are ionized, and these helium ions then fly into the ion trap, where the ion current is measured and recorded. The leak rate is then calculated using the ionization current.

Benefits of Helium Leak Testing

• Identification and measurement of leaks with high sensitivity.
• The majority of the testing is done in a dry, temperature-independent environment.
• Reduced cost and processing time with shorter cycle time.
• Due to the inert properties of helium, no effect on the substances under test.

Helium mass spectrometry is ideally suited for determining the intrinsic integrity of a packaging system. Helium mass spectrometer leak detection system for foil pouches offered by LDA (a PTI company) can be used to identify both large and small leaks. These are often employed in a vacuum chamber containing a sealed container filled with helium. Because of its non-toxic nature, helium is one of the important gases that may be used to identify leaks.

Food and Drug Administration (FDA) requirements for drug testing of combination products are strict. Companies seeking FDA clearance for such products must fully understand the requirements for FDA approval in order to prevent costly and time-consuming errors. Combination products are made up of two or more regulated components, such as pharmaceuticals, devices, or biologicals, that have been physically, chemically, or otherwise combined and formed as a single entity to achieve a therapeutic effect. A combination product can combine at least two of these product categories, and sometimes all three. Traditional drug-device combination products, such as a syringe pre-filled with a drug, auto-injectors containing a filled cartridge and needle, and co-packaged or kitted products, are some of the most common types of combination products.

The constantly increasing demand for combination pharmaceutical products continues to fuel innovation and creates numerous interesting opportunities that will provide the medical community with promising new alternatives for improving patient care and results. However, bringing bio/pharmaceuticals and medical devices together to form a combination product necessitates extensive testing of all product ingredients.

Why Use SIM 1915+ for Leak Testing Combination Products?

A Helium-based leak detection system-Seal Integrity Monitoring System (SIMS) 1915+ is an excellent solution for detecting leaks in combination products. Packages may be quantitatively evaluated using helium as the tracer gas, which assures better levels of accuracy when compared to traditional vacuum bubble and dye penetration test procedures. SIMS 1915+, which has been proven to be an effective leak detection approach, may also be utilized for package design, tooling certification, manufacturing line setup, and ongoing product quality monitoring. LDA custom builds each SIMS 1915+ Helium Leak Testing device to customer specifications. Cold form blister cards, foil pouches, parenteral vials, syringes, pre-filled syringes, and unique medical devices can also be tested using SIMS 1915+.

Technology Overview

SIMS Model 1915+ helium-based leak testing system offered by LDA ( a PTI company ) is specifically designed for medical and pharmaceutical package leak detection. The SIMS 1915+ enables quantitative analysis of package systems at sensitivity levels as low as 1 x 10 -10 cc/s at room temperature. The Helium Leak Detector Module (HLDM), the most crucial component, is built within a Console Frame Assembly with a Stainless Steel working surface and an optional Dual Test Port Manifold. The consoles have a locking wheel and an articulating arm system for attaching the computer and peripherals, making the independent device simple to operate and maneuver.

The SIMS 1915+ Leak Detection System specs and add-on components are shown below.

• Helium Leak Detector Module (HLDM): Oil-Free, Production Version in Console Frame Assembly with Stainless Steel Working Surface and Dual Test Port Manifold.
• Vacuum Test Fixture Model (VTFM): a custom-made fixture for testing vial container samples.
• Head Space Analyzer Module (HSAM): Model VM-2 that includes three (3) Puncture Probes (two spares) for determining the concentration of helium in the headspace of vial containers.
• Integral Calibration Chamber (with Calibrant Gas Flow Meter/Controller) for HSAM Calibration and a Universal Holder for various vial diameters are offered.
• Helium Filling Device designed specifically for vial testing sample prep that allows vials to be filled with helium.
• Low Temperature (LT) Add-on devices created particularly for evaluating products in ultra-cold storage temperatures as low as –140 °C.

SIMS 1915+ Applications

Common applications of SIMS 1915+ include:

• Pre-filled syringes
• Vials
• Bottles
• Combination products
• Foil pouches
• Blister packs

Combination products provide a safe, effective, and convenient method of administering the drug or biologic therapies. The purpose of testing combination products is to obtain information to support the claim that all use-related hazards connected with the product have been reduced to the greatest extent possible. LDA is well-versed in the extensive testing requirements and regulatory criteria for bio/pharmaceutical products and medical devices, and provides complete testing services for these components, both individually and in combination.

Helium leak testing is a non-destructive method to verify the presence of a leak in a component or device by using helium as a tracer gas. Being a highly sensitive method, it measures the amount of helium escaping through the package and is stated as a leak rate. Helium leak detection using Seal Integrity Monitoring System (SIMS) 1915+ is widely used in pharmaceutical and medical device product package systems for quality checking. SIMS 1915+ enable quantitative CCI analyses of packages at a sensitivity level as low as 1 x 10-10 mbar/L/sec. This quantitative method enables direct comparison across multiple packaging materials and formats, production line settings, and stability storage conditions. Each SIMS 1915+ Helium Leak Testing device is custom-built to meet the specifications and packaging configurations of the client. The following are the SIMS 1915+ configurations for CCI.

• Headspace Analyzer Module (HSAM)
• Helium Leak Detector Module
• External Calibrated Helium Leak Standard
• Dual Test Port Manifold
• Vacuum Test Fixture Model (VTFM)

Quality Control Leak Testing using LDA's Head Space Analyzer Module

The Head Space Analyzer Module (HSAM) is a critical component of a Leak Detection Associates (LDA) custom helium leak testing system. The Model VM-2, created by Leak Detection Associates, is the most recent version of this unique device. The HSAM includes a probe, which is essential for determining the helium concentration in the headspace of the container system. This system is simple to use and operate since it has an Integral Calibration Chamber with a Calibrant Gas Flow Control Valve and a Universal Holder that allows multiple diameter systems to be evaluated. Leak Detection Associates will provide three (3) Puncture Probes (two spares) with each unit.

The optional vial filling component enables the test preparation of already-sealed vials by replacing the headspace gas with 100% helium. This module can be used to prepare samples at the moment of testing, after capping, or to prepare samples that have been stored for a period of time prior to testing. When combined with the VM-2, these unique attachments enable accurate and sample-specific readings that may be integrated into flexible study designs.

Uses of Helium Leak Detection

• Ensuring container closure integrity.
• Seal integrity monitoring during stability studies.
• Verify and predict shelf-life seal integrity.
• Useful in the early-stage drug product package system development.
• Selecting closure formulation and configuration.

LDA's Head Space Analyzer Module (HSAM) - SIMS 1915+ configuration ensures highly sensitive leak detection of pharmaceutical pouches. Cold form blister cards, parenteral vials, cartridges, pre-filled syringes, bottles, combination product systems, and medical device products are other applications.

Pharmaceutical containers can be tested for Container Closure Integrity (CCI) in a variety of ways. Blue dye test and bacterial or microbial immersion test come under traditional, probabilistic methods. Whereas Vacuum Decay, Airborne Ultrasound, MicroCurrent HVLD, and Helium Leak Detection belong to the deterministic group of test methods. Each approach has advantages and disadvantages that should be considered while selecting a test method for a certain container type. All the methods are not appropriate for all sample configurations. Some succeed in certain applications while failing in others. Nowadays, the pharmaceutical industry is moving away from the traditional blue dye and bacterial immersion test methods and approaching deterministic methods for CCI testing.

The helium leak rate method is proven to be a strong contender for many applications. Helium leak testing is described as the process of detecting leaks in various enclosed or sealed systems by utilizing helium as a "tracer" gas and measuring its concentration as it leaves due to leakage. Like most CCI methods, Helium Leak Detection is deterministic. This method is more sensitive and not prone to contamination as compared to traditional dye or bacterial immersion methods. Due to its highly sensitive nature, it is possible to detect extremely small leaks, which are not possible with other leak testing methods.

Validating Helium Leak Rate Method for Pharmaceutical Containers

Validation of a Helium leak rate method for pharmaceutical container closure integrity assurance required proof that this physical testing method was as excellent as, if not better than, microbial immersion challenge testing in detecting potential integrity problems. Helium leak rate and microbial challenge tests were performed on one lot of rubber-stopper, broth-filled glass vials, which include faulty vials with known leaks. Glass micropipettes (0.1 to 10 microns) were fitted into the sidewalls of the vials to prepare defective vials. A 10% seeded defect rate was present in the validation lot, with nearly 50% of the leaks having a predicted probability of failing a microbial challenge (> 10%). The test units were charged for 4 hours under 40 psi helium pressure to implant the helium tracer in them. After charging, the crucial leak rate was found to be 10(-7) standard cc/second, and test units with measured leak rates exceeding this value were considered helium leak rate failures.

Microbial immersion challenge was performed by immersing the test units for 24 hours in a bath containing 10(9-10) viable E. coli and B. diminuta organisms, followed by a 13-day incubation period at 35°C. Visually, microbial failures were identified. The mean failure rates of the helium and microbial leak test techniques were compared statistically. The average helium failure rate was 6.9%, whereas the average microbial failure rate was 2.8%. There was a considerable difference between helium and microbial failure rates. As a result, helium leak rate testing has been shown to be an acceptable pharmaceutical container/closure integrity method for container quality assurance.

The helium leak detection method is chosen to be one of the best techniques for ensuring the integrity of pharmaceutical containers. This technique may be used to test the inherent package integrity and the Maximum Allowable Leakage Limit (MALL) during package development. It is applicable to a wide range of package types, can locate leaks, and can measure leak flow rates directly.

Testing a pre-filled syringe is critical when it comes to developing and releasing safe injectables to the market. Pre-Filled syringes are becoming increasingly popular due to their efficiency and simplicity. In addition, they provide a more dependable and safe option for patients as they contain the exact dose. Container closure integrity test techniques can be utilized to satisfy the regulatory, quality, and safety demands of sterile drug products. During development, qualification, and stability testing, the FDA encourages sterile pharmaceutical manufacturers to employ established and deterministic methodologies to confirm CCI.

Ensuring Pre-Filled Syringes Integrity using SIMS 1915+

Seal Integrity Monitoring System (SIMS) Model 1915+ is a helium-based leak testing system specially designed for a variety of pharmaceutical and medical device product package systems. A pre-filled syringe is one of its applications. Vials, cartridges, and blister cards are other applications. Packages may be quantitatively evaluated to levels much above the vacuum bubble and dye penetration test procedures using helium as the tracer gas. This quantitative method supports the full lifespan by allowing direct comparison across multiple packing materials and formats, production line settings, and stability storage conditions. SIMS 1915+ allows for quantitative analysis of packages with a sensitivity as low as 1 x 10-10 mbar/L/sec and will offer meaningful data sets instead of simple pass/fail criteria.

Seal Integrity Monitoring System (SIMS) model 1915+ helium-based leak testing system from LDA includes an oil-free pump, detector, and integrated power system built for the pharmaceutical and medical device industries. The most important component is the Helium Leak Detector Module (HLDM), built into a console frame assembly with a stainless steel working surface and an optional dual test port manifold. The freestanding units are equipped with a locking wheel and an articulating arm system for attaching the computer and peripherals, making them easy to operate and move. Each SIMS 1915+ helium leak testing device is manufactured to the specifications and package configurations of the individual customer.

SIMS 1915+ Options

• Low-Temperature Add-on Systems LT 80 and LT 150 for ultra-cold CCI testing utilizing helium leak detection methods.
• Vacuum test fixtures come in a variety of sizes to meet all package types and sizes.
• Helium leak testing for non-vacuum chamber applications with custom test fixtures.
• External helium leak standards in a variety of leak rate ranges.
• Helium Sniffer Probe - for determining leak sites on a site-by-site basis.
• Vacuum clamps, O-ring seals, chamber gaskets, and other components.

Pre-filled syringes benefit the manufacturer as well as the patient. They help in reducing medication mistakes since they have fewer steps and are easier to use than empty syringes. SIMS 1915+, developed by Leak Detection Associates, is an effective technique for testing leaks in pre-filled syringes. End-users may utilize the technology to ensure that manufacturing and packaging processes are efficient and productive while still satisfying safety requirements, international regulations, and market quality standards.

Container Closure Integrity Testing (CCIT) is essential for maintaining the sterility and stability of sterile injectable products. The optimal test method varies depending on the product. CCI testing is used to determine if there is a leak between the contents of a container and its external environment. This can be done by identifying whether communication can be established between the contents of the container and its surroundings.

Pharmaceutical containers such as vials, syringes, cartridges, and blister packs are frequently tested as part of a stability study to ensure that the closure of the container can maintain a sterile barrier. As part of a stability testing methodology, the Food and Drug Administration (FDA) suggests performing a container closure integrity test instead of a sterility test. Primary packaging methods based on vials for sterile pharmaceutical products must provide protection over the shelf life. This necessitates the demonstration of Container Closure Integrity (CCI), which should be done early in the pharma product development process. Helium leak testing is the most chosen CCI test method due to its high sensitivity when compared to other leak test methods.

What is Helium Leak Testing and How it Evaluates Vial Integrity?

Helium leak testing is one of the Container Closure Integrity (CCI) test methods for testing the leakage of pharmaceuticals and medical devices. This method uses helium and the change in concentration is detected when it exits owing to leakage. The applications of helium leak testing include vials, pre-filled syringes, foil pouches, or cold form blister cards. Each of these packaging types is meant to keep out harmful environmental pollutants such as dirt, microorganisms, or even gases while maintaining the sterility of the medicinal product enclosed. The package is filled with helium and subjected to vacuum in this method. A helium leak detector is used to quantify the amount of helium that escapes the package. The result is expressed as a leak rate.

Why Use Helium as a Tracer Gas?

Due to the following reasons, helium is considered an ideal choice for this type of testing:

• Helium is inert, and it is one of the smallest gas molecules.
• Small atomic size allows it to breach pathways reliably and easily.
• Helium is non-toxic, non-condensable, non-flammable.
• Safe to use as it will not interact with the components being tested.
• Helium is less expensive and readily available when compared to other tracer gases.
• The presence of helium in the atmosphere is not more than 5ppm.

As a highly sensitive quantitative test technique, helium leak testing evaluates Container Closure System (CCS) components for parenteral applications. It offers quantitative leak rate data that significantly exceeds the detection limitations of conventional approaches. The method has proven to analyze the impact of processing factors on container closure systems, such as parenteral vial capping applications, elastomeric closure selection, or changing sealing parameters.

The use of pre-filled syringes (PFS) as a container solution for pharmaceutical products has increased significantly in recent years. It is expected that this trend will accelerate in the future decades. Pre-filled syringes have the benefit of reducing pharmaceutical waste and extending the life of the product for the pharmaceutical industry. In general, pre-filled syringes are recognized as an effective, reliable, and convenient way to dispense drugs. In addition, many injections can be self-administered without worrying about being completely transferred from a vial. It provides a safe and effective option for patients in need of long-term pharmaceutical therapies.

When compared to the conventional vial, pre-filled syringes provide extra complexity in the field of container closure integrity (CCI) inspection. The advantages of pre-filled syringes include ease of use compared to conventional vial packaging. Pre-filled syringes eliminate the necessary procedures before you use the drug in a vial. In addition, since pre-filled syringes contain the correct dose, it helps to avoid dosing errors.

Leak Testing Pre-Filled Syringes Using Helium Mass Spectrometry

The device that detects and monitors leaks within and outside a product is called Mass Spectrometer Leak Detector. This approach makes use of helium as a tracer gas, which is utilized to fill a product coupled to a detector. Helium mass spectrometry is widely known for its suitability for non-porous packaging like vials and pre-filled syringes.

The leak detector works on the basis of a sector field mass spectrometer. In a vacuum, analyzed entering gases (Helium) are ionized. Helium ions are accelerated and separated in a magnetic field using increased voltage. Using a specific detector, the ion current is converted to an electric current. The current is accelerated and displayed on the screen by leak detection units. The current measured is proportional to both, the helium concentration and the measured leakage.

Benefits of Helium Leak Testing

• Leaks may be detected and quantified with a high degree of sensitivity.
• Due to the inert properties of helium, it does not affect the substances under test.
• The testing is mostly conducted in a dry, temperature-independent environment.
• Helium leak testing has a shorter cycle time, which lowers the cost and overall processing time.

For non-porous packaging including vials, pre-filled syringes, and cartridges, helium mass spectrometry has emerged as the new leak detection standard. Unlike probabilistic traditional methods, helium leak detection methods are preferred by manufacturers and regulators for their high sensitivity, fast test time, and detection capability. Pharmaceutical industries usually choose this process during the evaluation and eligibility stages of a new packaging process, where MALL plays an important role.

Foil pouches are commonly used when a product requires multi-layered packaging. They are utilized as the innermost layers of packaging. Since the foil pouches come into direct contact with the packaged product, they must be of the highest quality and extremely hygienic. They are typically composed of aluminum and are used to protect products from high temperatures. Furthermore, foil pouches have a low moisture vapor transfer rate. Foil pouches usually contain three to four layers. The higher the number of layers, the higher the pouch quality. Each extra layer increases the strength of the pouch.

Foil pouch integrity testing offers a unique set of challenges. The occurrence of foil punctures is an issue in most packaging techniques that use foil as the product barrier. These imperfections can occur when the foil is rolled into thin sheets and microscopic particles are rolled into the foil by mistake. Handling of the packages during the assembly of the foil and insertion of the drug product is the most typical source of the defect. Although the human eye can only reliably spot punctures bigger than 100 µm, these faults are difficult to identify. Punctures smaller than this can cause substantial ingress and, as a result, affect the effectiveness of the product.

How to Inspect Foil Pouches for Quality Control Using Helium Leak Test?

A highly sensitive method of detecting leaks in enclosed systems by using helium as a "tracer gas" is known as helium leak testing. Pre-filled syringes, foil pouches, and cold form blister cards are the most common applications of helium leak testing. Each of these package types is meant to keep out harmful environmental pollutants including debris, germs, and even gases while maintaining the sterility of the drug product inside. The leak rate is calculated from the amount of helium that escapes from the package.

The sensitivity of the helium leak detection methods makes it an ideal platform for quality control testing foil-based packaging systems. The test technique is designed to identify helium that has been trapped in the packaging system and has leaked via micro-voids in the pouch. Placing the foil pouch in the custom-designed test fixture and drawing a vacuum is the first step in a test sequence. Helium thus escapes through possible defects in the package as a result of the resultant pressure difference. The flow is directed to the analyzer cell at vacuum pressure, where the escaping helium gas is measured in the cell.

The average test cycle time is between 20 and 60 seconds. The test chamber is evacuated to the environment when the test cycle is completed and the measurement is recorded, and a new sample can be tested. The LDA HSAM helium concentration device is used to detect the helium concentration value of each pouch once all samples in the designated set have been tested. This approach normalizes the helium leak rate to 100%, allowing direct comparison of all test samples as well as the manufacturing line configuration.

Helium leak testing, one of the most commonly used CCI testing methods, is used to accurately determine the tiniest of the leaky opening in the foil pouches. Using this method, leaks can be quantified and detected with a high level of sensitivity and quality control testing. The Food and Drug Administration- FDA has long recognized helium leak detection as a consensus standard for package integrity evaluation.

The integrity of the seal between the container and the closure is a major concern when choosing packaging components for a parenteral drug product. The packaging must protect the pharmaceutical product from a number of possible sources of contamination, such as microbial ingress. Container closure integrity (CCI) is defined as the capacity of a container closure system to preserve a drug product and hence retain its efficiency and sterility throughout its shelf life. The purpose of container closure integrity testing is to determine the effectiveness of packaging closure.

To ensure CCI of pharmaceutical drugs, a number of methods are used. Helium Leak Detection is one of them. In this method, helium is used as a tracer gas, to detect leaks. This testing produces quantitative data that are more repeatable and reliable than qualitative pass/fail results. Despite the fact that it is a destructive test, helium leak testing is widely used because of its sensitivity and ability to run samples at temperatures below ambient. After the sample is prepared, it may be kept and analyzed at the proper temperature.

CCI Testing of Pharmaceuticals at Low Temperature

The CCI of pharmaceuticals may be determined using a variety of approaches. Under sub-ambient temperature circumstances, several methods of container closure integrity testing, such as blue dye ingress, microbial ingress, and vacuum decay, are insufficiently sensitive or simply unsuitable. Helium leak testing is a reliable method for testing closures and ensuring product effectiveness and sterility. This method is more sensitive than other CCI testing methods.

LDA has created the LT80, Low Temperature -80°C, Add-On test system for use with the LDA SIMS helium leak detectors to meet the market demand for analyzing leaks at cold temperatures. Concurrent temperature conditioning, temperature monitoring, and helium leak testing of packages approaching -80°C are all possible with the LT80 system. Even at temperatures as low as –80°C, helium leak detection is an effective method to ensure container closure integrity. While there are alternative methods for measuring CCI, many of them are ineffective at temperatures below –80°C. The LT150 low-temperature add-on unit allows for sample testing at temperatures as low as -150° C. The highly sensitive nature of the instrument allows for leaks as low as a 2µm hole can be recognized as a failure. The quantitative results provide the analyst with a numerical value, which allows for better data trends and greater confidence in the packaging system's performance than qualitative techniques can provide.

Container closure integrity or CCI, on packaging for parenteral drug products, is crucial for drug product preservation. The packaging closing components must be carefully chosen in order to eliminate sources of contamination that could harm the pharmaceutical product. The need to extend container closure integrity testing into the cryogenic temperature range is already becoming apparent. Container closure integrity must be achieved at cryogenic temperatures if pharmaceuticals are to be kept at cryogenic temperatures. For these types of drug items, newer packaging solutions like prefilled syringes and complex self-dosing devices are increasingly being used, and CCI will need to be proved for them as well.

Helium Leak Testing is used to locate and identify extremely tiny leaks in any component that can produce a differential pressure. Helium Leak Rate can be expressed quantitatively (the quantity of leak rate). The helium leak testing method is also used to examine the performance of a component or system, as well as to study or evaluate the lifetime of a product. Helium gas is primarily utilized as a leak testing medium due to its ability to detect and quantify leak rates at very low levels.

LDA offers various helium leak testing services for pharmaceuticals and medical devices. The services are as follows:

Leak Testing Services

• Installation & Quality Assurance of Helium Leak Detector

Leak Detection Associates guarantees that each custom instrument comes with comprehensive service delivery, installation, and validation program that is appropriate for the regulated environments in which the instruments will be used. Prior to delivery, the LDA Engineering Technician will collaborate with delivery site personnel to confirm that the location has the appropriate gas and electrical supplies for instrument functioning. Once the instrument is on-site and in the position specified by the customer, the Engineering Technician will perform a formal Installation Qualification (IQ), Operation Qualification (OQ), and Performance Qualification (PQ). Prior to execution, these can be pre-approved by local Quality Assurance.

• Helium Leak Detector Service Agreement

Leak Detection Associates recognizes that maintaining instrument performance is an important part of the business’s success. While the instruments offered by LDA are simple to use and maintain, it helps to improve productivity by proactively guaranteeing performance with an LDA Annual Service Agreement. Leak Detection Associates provides service contract plans that are customized to the unique needs and specifications. The following are examples of key components of any service program:

1. Repair and replacement parts are available on-site at no additional charge

2. Annual On-Site Preventative Maintenance

3. Detailed Annual Requalification & Calibration

•  Helium Leak Detector Calibration Services

Annual calibration services for all components of the test system, including internal and exterior leak standards and HSAM probes, are also available as an alternative to a full-service contract. Failure to calibrate the leakage criteria may result in a decrease in the accuracy and validity of the results over time, as well as concerns of individuals working in a CGMP or other controlled environment. A complete calibration program at regular intervals is designed to ensure proper instrument readings for the life of the device with minimal instrument downtime. LDA can set reminders when service is required once in our calibration database, ensuring that SIMS 1915+ does not skip a beat.

• Training for Helium Leak Testing

Leak Detection Associates offers on-site training relevant to how the SIMS 1915+ Helium Leak Testing device will be utilized, with the objective of being a comprehensive solutions provider to the clients. More sophisticated parts of leak testing, as well as system care and maintenance, can be covered in training programs. The Leak Detection team has over 20 years of hands-on expertise and can help the organization with anything from basic knowledge and understanding of leak testing basics to specialized leak test method development and validation.

• Helium Leak Detection Feasibility Studies

LDA offers dependable feasibility and method development services. Prior to procuring an instrument or moving on with outsourcing solutions, feasibility services can provide proof of concept for its intended usage, or they can assist to expand existing capabilities by designing solutions for new package systems. LDA also provides full method development utilizing industry-standard positive control techniques in the cases where clients do not have internal resources experience in the development of helium leak detection tests, or where current resources need to be expanded. Methods created at LDA can be transferred and verified at the client site, or they can be utilized frequently at LDA for lab-scale, non-cGMP research.

• Onsite or In-House CCI for Package Systems

LDA offers testing capabilities at both the client's site and our location. A SIMS 1915+ purchased and installed in a controlled context can be used for client onsite testing. With hands-on expertise in cGMP and regulated laboratory and production environments, documentation procedures are quite often in line with internal and external quality standards. LDA also provides the option of bringing one of our test units to a client's site for particular investigations. In-house testing is an alternative for clients looking to analyze package systems or designs on a contract basis.

LDA provides its customers with the highest quality of services. We are the world's leading manufacturer of high sensitivity helium-based leak detection systems for the pharmaceutical and biologic industries. Our engineers and support staff are highly trained and certified, allowing us to provide professional services across a wide range of testing domains.

Blister packages are a convenient format for users and a practical way to keep tablet and capsule quality preserved. The majority of blister package applications are considered low-risk, and they do an excellent job of protecting pharmaceutical products from moisture intrusion, which can cause product degradation. Tablets with a hydrophilic nature, or a natural tendency for absorbing moisture, require extra protection.

Due to an increase in the number of hormone-based and steroidal therapies in recent years, worries concerning the integrity of blister packing have emerged. Given their propensity to degrade and impair treatment outcomes, packaging these and other groups of pharmaceutical products is considered a high-risk application. To combat this, most manufacturers choose a totally aluminum, cold-formed package, which offers the best protection against oxygen penetration, while some industries have packaged very sensitive steroidal therapies in thermoformed blister packaging. As these products are more susceptible to environmental conditions than most other tablets and capsules, it is critical to inspect for tiny leaks, regardless of the packaging utilized in this high-risk application.

Limitations of Blue Dye Test

One or more blister packs are submerged in a chamber holding blue liquid and a vacuum is drawn to conduct the blue dye test. The chamber is then restored to atmospheric pressure, and the packages are retrieved and examined to determine if any dye has entered them. No defect is detected if there is no dye in the blister packaging. The blue dye only enters the package after the vacuum phase, which is the major defect of this method. As a result, when the chamber is returned to atmospheric pressure, nothing prevents the operators from removing the packages from the dye during this final stage.

Package headspace and dye surfactant concentration are the other difficult factors to control in the blue dye test. In reality, the test just determines how easily or quickly the dye may enter the blister cavity. It does not tell you about oxygen or vapor intrusion. This is a significant disadvantage since gaseous pollutants may penetrate foil and film more readily through a tiny leak, which is subject to surface tension. This requires a relatively large single passage to enter the package. Another major disadvantage and difficulty to control is the subjective nature of the operator's inspection.

Leak Testing Blister Packages Using Deterministic Test Method

Helium leak testing is a deterministic method for identifying package leaks in blister packs using helium as a tracer gas. The change in its concentration is measured as it escapes due to leakage. The quantity of helium that escapes from the package is expressed as a leak rate. Helium leak detection is a very sensitive technique for testing pharmaceutical package integrity.

Seal Integrity Monitoring System (SIMS) 1915+ is the optimum leak detection system using helium. When compared to traditional methods such as vacuum bubble and dye penetration test, packages may be quantitatively examined with high accuracy. This method enables a comparison of different packaging materials and forms, as well as production line settings and storage conditions, thus supporting the entire life cycle. Package design, tooling qualification, production line setup and ongoing product quality monitoring are the applications that come under SIMS 1915+. It is specially designed for the pharmaceutical and medical device industries.

Blister packaging is a type of pre-formed plastic packaging that includes a base card with artwork and a clear plastic pocket called the blister. The cavity, which is composed of either plastic or aluminum foil, and the lid, which is made of paperboard, paper, plastic, or aluminum, are the two main components of blister packaging. The product is enclosed in the cavity, and the lid seals the package. Blister packing is used in the pharmaceutical industry to pack tablets, pills, capsules, granules, and lozenges. Blister packaging gets its name from the fact that each item is kept within its own small plastic bubble or blister. Blister packs can provide tamper resistance as well as barrier protection for shelf-life requirements.

Due to its extreme sensitivity, a helium-based test method is used for verifying the integrity of the blister pack. The test method operates by detecting helium that has been enclosed in the package system and is escaping through micro-channels in the package. This test sequence begins with the package being placed in the test fixture and immediately drawing a vacuum. The helium thus escapes through potential holes or cracks in the packaging as a result of the pressure differential.

Blister Pack Leak Testing Using Helium Mass Spectrometry

The Mass Spectrometer Leak Detector is a comprehensive system for locating and detecting leaks within or outside of product. This approach employs the use of helium as a tracer gas, which is utilized to fill the product attached to the detector. Helium leaks into and out of the tested product, causing its partial pressure to be measured and shown on a screen.

The leak detector works on the principle of a sector field mass spectrometer. Helium gas is ionized in a vacuum. Helium ions are accelerated and separated in a magnetic field using additional voltage. The ion current is converted to an electric current using a specific detector. The current is accelerated by leak detection units and displayed on the screen. The measured current is proportional to the helium concentration and equal to the observed leak. Helium leak detection using helium mass spectrometry is widely known for its suitability for packaging such as blister packs.

Helium Leak Detection Benefits

• With a high degree of sensitivity, leaks can be identified and measured
• No effect on the materials under test, due to the inert properties of the helium
• The testing procedure is mostly dry and temperature-independent
• Helium leak testing has a faster cycle time, which reduces the cost and overall processing time

Helium leak detection offered by Leak Detection Associates (LDA) can greatly improve the safety and health of blister package users. Blister packaging ensures that tablets and capsules are properly sealed. It is simple to do a leak test after packaging. Blister packaging is popular because of its convenience of packing, easy dosing for the patient, with its popularity increasing for many new drug solid dose/oral dose products.

LDA, the global leader in helium-based leak detection systems for the pharmaceutical and medical devices industries. Helium leak testing is a technique for locating and identifying leaks in a closed vessel using a tracer gas, helium. The method of helium leak testing is often used to evaluate system performance. Helium gas is commonly employed as a leak testing medium because of its ability to detect and quantify leak rates at extremely low levels.

SIMS Version 1.11.19 21 CFR Part 11 compliant software program

SIMS Version 1.11.19 21 CFR Part 11 is a compliance software application particularly created and manufactured for custom-built helium leak testing equipment. The application was created to support SIMS 1915+ units and makes LDA the only helium-based leak testing system provider on the market that meets all the FDA's (Food & Drug Administration’s) 21 CFR Part 11 data integrity software criteria.

With the growing usage of computer systems and electronic records over the last two decades, the FDA has published a number of guidance documents and directives outlining particular requirements for electronic data management. Users must be able to log in at different levels, utilize electronic signatures and approvals, have secure data management that prohibits changes to current results, and have an electronic audit trail that captures all relevant activities in a time and date stamped pattern.

LDA was able to build a robust and thorough helium leak testing procedure on our custom-designed and built systems. This improves functionality and usability compared to existing software options, by contracting with a development team that specializes in the development of instrument operation software programs and has extensive experience in the Part 11 area. LDA is offering a system software update program for current SIMS devices in the market for quick onsite installation for a client's existing installation base. The 21 CFR Part 11 program consists of all the instruments, including SIMS 1915+ and SIMS 1915+ LT low temperature add-on units.

Leak Detection Associates has been the major provider of custom helium leak detection equipment to the pharmaceutical, and medical device industry for over 20 years. Based on intended usage and target package system configuration, each test system is developed to meet regulated quality system requirements as well as the particular client's specifications. The LDA team creates custom add-on components for clients that need a flexible leak detection system that can be used with a variety of package types and configurations. This ensures flexibility in reaching particular research goals.

Helium leak detection is referred to as the process of detecting leaks in various packaged or sealed systems by utilizing helium as tracer gas and measuring its concentration as it escapes due to leakage. A package system such as a vial that consists of a container and an elastomeric closure, is a good example. The vial is filled with helium and vacuum is applied. The quantity of helium that escapes from the package is quantified and expressed as a leak rate. A pre-filled syringe, a foil pouch, or a cold form blister card are some more examples of package systems. Each of these package types is designed to keep the pharmaceutical product enclosed while keeping out potentially harmful environmental pollutants like dust, bacteria, or even gases. The helium leak testing method can evaluate each of them.

Helium leak testing is widely utilized in the pharmaceutical and medical device industries because of its relevance in guaranteeing package integrity and quality. Now, let us see how these sectors benefit by using this technique.

1. Pharmaceutical Industry: The pharmaceutical industry has experienced enormous progress in terms of technological developments and drug delivery system innovations over the last two decades. However, such developments have created new quality assurance challenges for drug manufacturers. As a result, pharmaceutical manufacturers give major priority to both quality control procedures and pharmaceutical package leak detection.

CCI Testing is a leak detection technique that evaluates the capacity of container closure systems to maintain a sterile barrier against external contamination. These tests may be divided into two types: probabilistic test and deterministic test. Although probabilistic test methods like Bubble Tests and Dye Ingress were initially common, due to technological advancements, non-destructive approaches are now the preferred way for ensuring container integrity. Hence, pharmaceutical manufacturers are encouraged to switch to more dependable deterministic test methods, such as helium leak detection, which offer quantitative findings that are assured and precise. By using helium leak detection early in the development process, companies can improve the quality of their drug delivery system. This not only saves money and time, but also improves safety.

2. Medical Devices Industry: In the medical device industry, package integrity testing is important since product failure presents considerable risks to patients and healthcare professionals, as well as liability for manufacturers. Barriers between fluids or gases are frequently used in medical equipment. These barriers must be functional in order to safeguard the patient and, in many cases, the medical equipment. Some devices operate as channels for delivering or extracting fluids to or from specific parts of the body. If a leak develops along the channel, fluids might be supplied to the incorrect place by mistake or wrong fluids could be extracted, resulting in hazardous effects. As a result, medical device industries use various CCI test methods including helium leak testing to ensure package integrity.

Helium leak testing is the most common tracer gas method in the medical device industry. Helium or a helium-air combination is used to pressurize the test component within a vacuum chamber. The chamber enclosing the part is next evacuated, generating a vacuum that allows the helium to enter the chamber through any leaks. A mass spectrometer designed to detect helium takes a sample of the vacuum chamber and ionizes any helium detected. Even a small amount of helium is easily detected in this method.

The major reason for choosing the tracer gas technique by manufacturers is the necessity for high leak-detection sensitivity in particular medical device equipment applications. Product testing is a crucial part of the device production process in the medical industry. As quality requirements have gotten increasingly strict, leak testing has become increasingly important for medical equipment as well as pharmaceutical manufacturers.

Helium leak detection technology is used to identify tiny leaks in a contained system. Other detection techniques may not be applicable due to operating limitations or if the leaks are so small that other techniques cannot find them. Due to its tiny size and inert nature, helium is an excellent choice for testing purposes. It has no effect on the materials in the item to be tested. Because of a variety of factors, helium is a preferable option as a tracer gas.

• Non-toxic, inert, and non-flammable
• The tiny atomic size makes it easy to pass through leaks

Helium is detected with a mass spectrometer or helium sniffer, however, it is also possible to utilize a residual gas analyzer. In comparison to other methods of finding leaks, helium testing is a thousand times more sensitive.

Various technologies

• SIMS 1915+

SIMS 1915+ is the ideal option for helium leak detection in pharmaceutical and medical device packaging systems. Vials, syringes, cartridges, and blister cards are some of the most common applications. Helium is commonly used to test the rubber stopper on a vial or the plunger on a syringe or cartridge assembly for leaks in parenteral goods. Sensitivity level as low as 1 x 10-10 mbar/L/sec may be measured with SIMS 1915+, which offers useful data sets instead of a basic pass/fail condition while allowing testing to be done at ambient temperature. It is important to note that each SIMS 1915+ Helium Leak Testing device is custom-built to meet client-specific requirements and package specifications.

• Cold storage package test systems

In an effort to retain product quality features, pharmaceutical and biologic firms continue to push for extended cold storage. In addition to requiring storage at temperatures below -20°C, many of these goods also require dry ice (-78.5°C) or liquid nitrogen (-200°C) for storage and delivery. However, many of the materials utilized in these package systems and responsible for preserving package integrity are not routinely evaluated at these temperatures. The glass transition state of elastomeric materials can be reached or exceeded at deep-cold or ultra-cold temperatures, causing leaks at low temperatures that would not otherwise be detected at room temperature.

• HSAM and Vial Filler

When it comes to helium-based leak testing systems, the Head Space Analyzer Module (HSAM) with vial filling assemble is a key component. As part of the HSAM, a probe measures the helium content in the headspace of a container system. With the optional vial filling assembly, previously sealed vials may be prepared for testing by replacing the headspace gas with 100 percent helium before the test is performed. After capping, this module can be used to prepare samples for testing or to prepare samples that have been kept for some time before testing. They may be used in conjunction with the VM-2 to get precise readings that can be included in flexible research designs.

• Sniffer Probe

This simple technique of tracer gas leak detection employs a sniffer probe to detect the gas's presence and locate the location of the leak. The tracer gas is initially applied to the part or system. With the sniffer probe, the operator then conducts a systematic search for probable leak spots. When it comes to finding micro leaks, sniff leak locating is quite successful. It is best used for examining smaller quantities of items. While the cost of sniffer testing depends on the kind of tracer gas utilized, it is a proven option for leak detection and localization.

• Package Test Fixtures

Outside the box, no leak testing is possible using a Helium Leak Detector. An HLD is only one component of a matrix that makes a useable system, just like a display is part of a computer system. Checking for quality packing material and sealing is a part of testing a package. By squeezing and holding it underwater, an operator checks for bubbles in a package using the manual leak testing method. The package retains atmospheric pressure when there are leaks.

• Calibrated Leak Standards

To support everyday usage, daily performance verification or system suitability tests, as well as planned certifications, LDA supplies full sets of calibrated helium leak standards. Each SIMS 1915+ has an inbuilt helium leak standard. Using a given leak rate, this technique releases a certain concentration of Helium. On each day of usage, it is utilized automatically by the instrument, or on-demand for autocalibration prior to analysis. Each external helium leak standard by LDA releases helium at a defined leak rate, similar to the internal leak standards. But instead of living inside the instrument, they attach to the test port in the same manner that a sample fixture would be installed in the system.

Some basic applications

• Glass Vials
• Pre-filled Syringes
• Bottles
• Blister Packs
• Foil Pouches
• Combination Products

Helium leak detection technology is a highly sensitive method used for detecting leaks in an enclosed system. Helium is used as a tracer gas as it is inert, non-condensable, non-flammable, and harmless. Because of its small atomic size, helium passes easily through the leaks. Thus, the change in its concentration is measured and indicated as a leakage rate. Helium is lighter than the next inert gas neon. It is also very cost-effective and can be easily delivered in various cylinders and in pure form. Hydrogen that is not inert is the only molecule smaller than helium.

Helium leak detector works on the principle of field mass spectrometer. The electric beam in the filament of the analysis tube ionizes the leaking helium gas. The ions are accelerated by increased voltage, escape through the split and later pass through the analyzer's magnetic field. The collector can only catch the helium ions and detect helium, as the circular paths of the ions rely on their mass. The ion current is transformed into an electric current using a specific detector. The current is accelerated by utilizing leak detector devices and displayed on the screen. The measured current is equivalent to the concentration of helium and hence equal to the leak.

What makes helium gas ideal for package leak testing?

• Non-toxic, inert, non-condensable, present in the atmosphere in trace amounts
• Helium gas is one of the smallest molecules to consistently and rapidly break the pathway
• Helium is non-flammable, widely available, and inexpensive
• Since it is an inert gas and does not interact with the testing component, it is, therefore, safe to use
• The noise of the instruments caused by the environmental helium is naturally minimal due to its low atmospheric level of less than 5 ppm and thus gives accurate reports

Key benefits of helium-based testing

• Helium leak detection is a highly sensitive detection technique, particularly developed to identify extremely small leaks which cannot be detected with standard leak test methods
• The leak test limit may be set at a level of 1 x 10-10 mbar L/sec, which enables unique comparisons across components, materials, formats, and manufacturing characteristics using a high-speed vacuum approach

Applications of Helium leak detection

Following are some of the common applications of helium leak detection technology:

• Glass Vials

One of the most common package systems for biotechnological and pharmaceutical products. Helium is the most appropriate and sensitive way for qualifying components for empty components and for product-filled vials.

• Pre-filled Syringes

Pre-filled syringes represent the biggest growth area of parenteral packages with the development of more sophisticated drugs for a wide range of injectable substances and increased demand for self-administration. Helium testing techniques can be developed such that these unique package systems have extremely effective test programs.

• Bottles

Bottles are one of the most used packaging methods and helium still remains the standard for quality testing purposes.

• Blister Packs

Helium is still the optimum test technique for qualifying the CFF blister cards' material components. The test procedure is based upon the detection of helium encapsulated in the packaging system as it escapes from the package via micro-channels.

• Foil Pouches

The sensitivity of the helium leak testing method provides an excellent platform to test quality control systems based on foil. This technique normalizes the helium leak rate to 100% so that all test specimens throughout the manufacturing line setup may be directly compared.

• Combination Products

Multi-chamber systems with specific needs for tests are perfectly suited for using helium leak test to guarantee that all components satisfy the rigorous leakage standards.

Like vials package systems, bottles whether composed of plastic materials or glass, continue to be one of the most widely used package systems and Helium remains the gold standard for quality testing purposes.

Evaluating seal integrity of bottles or containers used for liquid contents is what ensures the quality of the bottles surpass the quality parameters. Seal integrity testing of bottles is done to ensure that the contents of the container do not leak out in any condition. As weak seals, partial seals or no seals can occur in the final sealing stage, manufacturers often conduct high-quality seal integrity tests that guarantee reliability and quality of bottle seals.

Thread shape, mating surface shape, and composition of the material used for making the container and the closure are common factors that can affect the seal integrity of bottles. An ideal seal can be generated if the container and closure materials are made up of distinct composition. Seal quality can also be affected by time-dependent factors. This is especially possible if containers, closures, or both are constructed using plastic resins. Similarly, exposing the bottle and its contents to freezing temperatures can affect the seal via expansion and contraction of the materials in threads and mating surface area.

Before dispatching, leak detection of sealed containers is a crucial vital step to ensure container’s seal integrity, food and nutrition, medical device and pharmaceutical industries require highly sensitive leak testing techniques to measure seal strength of the containers. One such method is helium leak detection.

Overview of helium leak testing?

Helium leak testing refers to the process of finding leaks in some type of enclosed or sealed system using helium as a “tracer” gas and measuring its concentration as it escapes due to leakage. It is an effective container closure integrity test method, aimed at evaluating the integrity of pharmaceutical and parenteral products. Helium leak detection works in the following way: Initially, the package is helium filled and subjected to vacuum. Then using a helium leak detector, the amount of helium escaping the package is quantitatively measured and stated as a leak rate. Apart from analyzing container closure integrity, helium leak testing is also applicable in product design, product quality analyses, failure analyses and validation. Helium leak testing is a flexible method that can be used with or without a test chamber in order to test "in-leakage" or "out-leakage", as well as leak location.

Why use helium as a tracer gas?

Helium is considered as an ideal choice of tracer gas because of the following reasons:?

• Helium is non-toxic, non-condensable, non-flammable.
• It is inert, making it safe for use as it will not interact with the components being tested.
• The atom size of helium is really small, allowing it to breach pathways reliably and easily.
• Compared to other tracer gases, helium is less expensive and readily available.
• Its presence in the atmosphere is not more than?ppm.

Pharmaceutical product manufacturers use packaging materials that offer optimal protection and safety allowing to extend product shelf life. Cold form blister packs are manufactured by sandwiching aluminum foil between Polyvinyl Chloride and nylon films using dry bond lamination technology. They provide complete barrier to moisture, light, oxygen, and other gasses. Its ability to offer complete product integrity and protection has made it a favourable choice for pharmaceutical industry.

Oral and solid dose manufacturers aim at producing high quality and cost effective alternatives while manufacturing innovative, convenient packs for end-users. Due to its high efficiency rate and the ability to provide extended shelf life, the cold form blister packs are being extensively used in healthcare packaging. Many pharmaceutical products including tablets, capsules, drugs, vials, ampoules, syringes or liquid products are often packaged using cold form blister packaging. Infact, growing requirements of pharmaceutical companies worldwide had led to the production of cold form foils such as push-through, peelable, peel-push, tear-open and child-resistant. However, the growing demand for cold form blister packs have accelerated concerns about integrity of blister packaging. Although the amount of environmental contaminants that can enter a package vary based on leak size, with blister packages, even minute leaks can become a problem. Depending on the pressure, temperature and duration of exposure, contaminants can easily find path in the seal or any other microscopic crack. Therefore, it’s important for manufacturers to conduct appropriate container closure integrity tests that ensure quantitative and reliable leak testing solution.

Helium leak testing is one of the most sensitive container closure integrity test methods, used primarily for evaluating integrity of critical parenteral or injectable products. In simple terms, it can be understood as the act of finding leaks in some type of enclosed or sealed system using helium as a “tracer” gas, and measuring its concentration as it escapes due to leakage. Apart from being an ideal solution for ensuring container closure integrity, the technology is also applicable in package design, monitoring product quality, failure analysis and line set up and validation.

Helium is considered an ideal choice of tracer gas because of multiple reasons. Helium is non-toxic, non flammable, non-condensable and its presence in the atmosphere is not more than 5ppm. The small atomic size of helium makes it easier to pass through leaks. Since helium does not react with other materials, it is relatively safe to use. Additionally, compared to other tracer gases helium is less expensive and is available in multiple cylinder sizes. Under this method, a helium leak detector otherwise known as Mass Spectrometer Leak Detector (MSLD) is used to identify and calculate size of the leak.The test part is first connected to a leak detector and then the tracer gas, helium is introduced. In the presence of a leak, helium escapes from the test parts and this partial pressure?is?measured and results are displayed on the meter

Applications of Helium Leak testing

• Ensuring Container Closure Integrity
• Using sniffer probe to identify sources of the leak
• Selecting closure formulation and configuration
• Seal integrity monitoring during stability studies
• Using proprietary software to predict shelf- life seal integrity

The global pharmaceutical industry has seen tremendous growth over the past few decades. However, complex nature of the industry coupled with frequent breakthroughs has made it a favorite subject of scrutiny. Adding to that, the COVID-19 pandemic has accelerated pharmaceutical industry challenges. Along with COVID-19 vaccine, the industry has seen a spike in the production of cell and gene therapy treatments, biologics, and other large-molecule products that demand unique storage conditions to maintain sterility of the drug throughout its shelf life or until it is administered.

Since most high-risk pharmaceutical products are filled and sealed in combination devices, it’s critical for manufacturers to ensure that the components function well together. Hence, design and distribution considerations are critical to the early design of both the drug and the container. Manufacturing inconsistencies and tolerance differences in packages containing multiple components are primary contributors to distribution issues. Often, such inconsistencies result in container closure failure, causing serious implications down the supply chain. For instance, glass vials and pre-filled syringes may not seal properly at critical fill-finish closure points. Such a failure can cause oxygen or other environmental contaminants to enter the product and compromise the efficacy of the drug in the barrel. At this point, it is critical to use the most precise leak testing method possible.

In such situations, helium leak detection is the most effective sensitive test for ensuring container closure integrity. By utilizing helium leak detection early in development, companies can make considerable improvements in the quality of their drug delivery system. This not only saves cost and time, but will also raise standards of safety.

Understanding helium leak detection technology

Helium is used as a tracer gas because it is non-toxic, non-flammable, non-condensable and its presence in the atmosphere is not more than 5ppm.Being the second smallest molecule on the periodic table, helium can expose virtually any opening. Further, helium does not react with other materials, so it is relatively safe to use. Under this method, a helium leak detector otherwise known as Mass Spectrometer Leak Detector (MSLD) is used to identify and calculate size of the leak. The test part is first connected to a leak detector and then the tracer gas, helium is introduced. In the presence of a leak, helium escapes from the test parts and this partial pressure is measured and results are displayed on the meter.

Applications of Helium Leak testing

• Ensuring Container Closure Integrity
• Selecting closure formulation and configuration
• Seal integrity monitoring during stability studies
• Extremely valuable in early stage pharmaceutical product package system development

What is helium leak detection?

Helium leak detection refers to the process of identifying leaks in an enclosed or sealed system using helium as a tracer gas. Helium is an ideal choice of tracer gas to find leaks because it is non-toxic, non-flammable, non-condensable, and its presence in the atmosphere is limited to 5ppm. Helium can pass easily through leaks because of its small atomic size. Additionally, helium is safe to use because it does not react with materials of parts being tested.

Overview of sniffer probe leak detection

Sniffer leak testing is a common tracer gas leak detection method that uses a sniffer probe to detect the presence of tracer gas and identify an area that is leaking. Under sniffer probe helium leak detection, helium is used as a tracer gas in combination with instrumentation to detect the presence of helium and more precisely an increase in helium due to the leaking part.

The prime objective behind conducting a sniffer probe leak detection test is to locate leaks in parts or systems so that they can be identified and repaired. The part or system is first pressurized with the tracer gas and then systematically scanned with a sniffer probe so as to detect possible leaks. Sniffer probe leak detection cannot be considered as a quantitative leak detection technique because the test results may vary depending on skill of the operator and the technique used. However, with the use of calibrated instruments, calibrated leak standards, and well-trained operators, quantitative results may be achieved. Sniffer leak testing is considered as an economical leak detection method that involves relatively low tool cost investment depending on the tracer gas used. Although sniffer probe leak testing is very effective in locating micro leaks, it may not be an ideal choice in high volume production environment.

How does sniffer probe leak detection work?

Sniffer probe leak testing begins by first filling the test object with tracer gas. The pressure inside the test object is increased to a pre-determined rate in order to create a differential in pressure. The outside of the test object is scanned using a sniffer probe that is connected to a leak detector. Because of the innate properties of helium, it readily penetrates through leaks and is sucked into the sniffer probe. The leak rate meter shows a display of the signal. On reaching maximum leak rate display, leak is located. Although the sniffer probe leak detection technique is very sensitive, its accuracy can be affected due to the amount of helium present in the atmosphere.

Advantages of Sniffer Probe leak detection

• Sniffer probe is very effective in locating minute leaks.
• Does not require expensive fixtures or test chambers and can be employed at low cost.
• Useful in testing small parts as well as complex systems.
• Higher test sensitivity can be achieved by increasing tracer gas pressure.
• Capable of detecting leaks in the range of 1.6x10-1 to 1x10-5 scc/s.

Container closure integrity plays an integral role in maintaining the stability of sterile pharmaceutical products. Most often, defects that cause vials to leak cannot be detected by a visual inspection process. Examples of such defects include microscopic cracks & scratches in the glass or temporary defects such as stopper pop-up that result in temporary container leakage. In such situations, helium leak testing ensures high sensitivity leak detection, which cannot be attained by many other leak test methods.

Overview of helium leak testing

Helium leak testing refers to the process of finding leaks in some type of enclosed or sealed system using helium as a “tracer” gas and measuring its concentration as it escapes due to leakage. It is an effective container closure integrity test method, aimed at evaluating the integrity of pharmaceutical and parenteral products. Helium leak detection works in the following way: Initially, the package is helium filled and subjected to vacuum. Then using a helium leak detector, the amount of helium escaping the package is quantitatively measured and stated as a leak rate. Apart from analyzing container closure integrity, helium leak testing is also applicable in product design, product quality analyses, failure analyses and validation. Helium leak testing is a flexible method that can be used with or without a test chamber in order to test "in-leakage" or "out-leakage", as well as leak location.

Why use helium as a tracer gas?

Helium is considered as an ideal choice of tracer gas because of the following reasons:

• Helium is non-toxic, non-condensable, non-flammable.
• It is inert, making it safe for use as it will not interact with the components being tested.
• The atom size of helium is really small, allowing it to breach pathways reliably and easily.
• Compared to other tracer gases, helium is less expensive and readily available.
• Its presence in the atmosphere is not more than ppm.

Glass vial leak testing using SIMS 1915+

Seal Integrity Monitoring System (SIMS) 1915+ is an ideal choice for helium-based leak detection of vials, blister cards, syringes, and cartridge systems. Compared to conventional vacuum bubble and dye penetration test methods, packages can be quantitatively tested using helium as the tracer gas that ensures higher levels of accuracy. Proven to be an affective leak detection method, SIMS1915+ can also be used for package design, tooling qualification, production line setup and on-going product quality monitoring. Designed specifically for the needs of pharmaceutical and medical device industries, SIMS1915+features an oil-free pump, detector and integrated power system that ensures quantitative analysis of package systems at sensitivity levels as low as 1 x 10 -10 cc/s at room temperature. Based on the client’s specific requirement, each SIMS 1915+ Helium Leak Testing instrument manufactured by Leak Detection Associates can be customized. Given below is a list of SIMS 1915+ Leak Detection System specifications along with add-on components.

• Helium Leak Detector Module (HLDM): Oil Free, Production version in Console Frame Assembly, with Stainless Steel working surface and Dual Test Port Manifold (allows concurrent use of VTFM & HSAM on HLDM unit).
• Vacuum Test Fixture Model (VTFM) – custom designed for use in testing of vial container samples
• Head Space Analyzer Module (HSAM) – Model VM-2 that includes three (3) Puncture Probes (two spares) for determination of Helium Concentration in the headspace of vial containers.
• Integral Calibration Chamber (w/ Calibrant Gas Flow Meter/Controller) provided for HSAM Calibration and a Universal Holder to be used for various vial diameters.
• Helium Filling Device specific for vial testing sample prep to enable vials to be filled with helium
• LT Low Temperature Add on units specifically designed for testing products under ultra-cold storage testing down to –140 °C.

Leak Detection Associates’ most current model, the Seal Integrity Monitoring System (SIMS) 1915+, is the ideal choice for your helium based leak detection system. Using helium as the tracer gas, packages can be quantitatively tested to levels far exceeding the vacuum bubble and dye penetration test methods. This Quantitative approach allows direct comparison across various packaging materials and forms, production line settings and stability storage conditions. The LDA SIMS 1915+ is a proven and effective tool for package design, tooling qualification, production line setup and on-going product quality monitoring of a variety of package types including cold form blister cards, foil pouches, parenteral vials, syringes, pre-filled syringes and unique medical devices.

Each SIMS 1915+ Helium Leak Testing instrument manufactured by Leak Detection Associates is custom built to client-specific standards. Key factors that determine instrument build specifications include:

What type of package(s) will you be testing with this instrument – Vials, Blister Cards, Syringes, Cartridge System or Medical Device? Size and closure type should be included and whenever possible a schematic of the package or device can be helpful in optimizing the test system.

Projected amount of use the instrument will see?

Country where the instrument will be installed?

Leak Detection Associates Seal Integrity Monitoring System (SIMS) Model 1915+ helium-based leak testing system features an oil-free detector and integrated power system that is designed for the needs of the pharmaceutical and medical device industries, enabling the client to quantitatively analyze package system at a sensitivity level as low as 1 x 10 -10 cc/s at room temperature. The most critical component, the Helium Leak Detector Module (HLDM), is engineered into a Console Frame Assembly that features a Stainless Steel working surface and Dual Test Port Manifold. The console has a locking wheel and will be fitted with an articulating arm system for mounting of the computer, monitor, key board and direct access printer, making the freestanding unit easy to use and maneuver.

The First Helium Leak Detectors

The genesis for the use of helium as a method for leak detection can be traced back to the 1940’s and the Manhattan Project. The first atomic bomb created used uranium isotope 235, which is taken by way of separation from uranium-238. The separation was accomplished in a huge “diffusion” plant using microporous tubing as the diffusion medium and this process needed to be done in a manner that prevented any trace of moist ambient air in the process chambers. In essence, it was imperative that all the equipment be free of any leaks. Equipment of this size and magnitude had never before been tested to such and extreme leak detection specification. A number of various leak detection devices were tried, and they all proved unsuccessful as they could not meet the required standard for sensitivity. Eventually, a simplified mass spectrometer based on the Nier 60 spectrometer tube was chosen for leak detection and helium was the gas of choice used with it. It was determined that helium flow as sensitive as 10−6 std cm3 could easily be detected.

Major Improvements in Helium Leak Detection

In the 70+ years since the inception of the Manhattan Project, helium leak detectors have understandably been drastically improved. The size of an actual helium detector that in 1945 required a large scale, multi-story warehouse building, can now fit on a standard laboratory benchtop and the level of detection has been improved to levels that meet or exceed flows rates of 10−10–10−11 std cm3. With the inception of computers, operation of a helium detector has been fully automated. Based upon these developments, the use of helium as a medium for leak detection has become common and wide-spread practice and thus has a presence in almost every conceivable industry from refrigeration, semi-conductors, automotive and food and drug packaging components.

Modes of Operations using Helium Leak Detection

Conceptually, the principle of operations has not changed much in the past 50 years although, as noted, the size has been drastically reduced. The central piece of the helium leak detector is the cell in which the residual gas is ionised and the resulting ions accelerated and filtered in a mass spectrometer. Most of the current detectors use, as in the original design, a magnetic sector to separate the helium ions from the other gases. Permanent magnets are generally used to generate the magnetic field. The adjustment needed for the selection of the helium peak is made by varying the ion energy. At the highest sensitivity range, currents as low as femtoamperes have to be measured. This is achieved with the use of an electron multiplier in the most modern detectors. If the cell of a leak detector is not much different from the original design, the pumping system has considerably changed with the original diffusion pumps now being replaced by turbomolecular pumps or dry molecular-drag pumps. The sensitivity of the helium leak detector is given by the ratio between the helium flow through the leak and the partial pressure increase in the cell. In order to increase the sensitivity, the pumping speed of the tracer gas has to be reduced. This must be done without diminishing the pumping speed for the other gases (mainly water as leak detection usually takes place in unbaked systems) in order to keep the appropriate operating pressure for the filament emitting the ionising electrons. Selective pumping is therefore needed to provide a high pumping speed for water and a low pumping speed for helium

We hope that you have learned something regarding the history of helium leak detectors. In future installments, we will address various test methods and case studies that will provide more specific insight into the use of helium applied to the package leak testing needs of the pharmaceutical and life sciences industries.

In a recent blog, we discussed the application of helium leak detection (HeLD) as part of a capping optimization study or assembly validation for glass and plastic vials. A defining characteristic of helium leak detection, instruments such as the SIMS 1284+ have sensitivity capable of measurement below the maximum allowable leakage limit (MALL) of many pharmaceutical and medical device products. This allows for study-based comparisons and data-informed decision making at a very fine scale. More importantly, these types of studies can be used to support regulatory documentation and in fulfillment of guidance such as USP <1207>.

While applications of this approach to vials are well established, if increasingly popular, very similar approaches can be taken for other common package systems used in the industry. Cartridges, which are frequently used as part of a device delivery system, are one such format. Similar to a traditional vial, one end of a cartridge is typically sealed with an elastomer-lined crimp. Compared to that of a 20mm or 13mm vial, cartridge crimp seals are relatively small and intricate. On the other end, a cartridge is typically sealed by an elastomeric plunger, similar to that which may be found on a syringe. Each of these unique sealing interfaces present specific challenges from a CCI perspective.

Considering the crimp interface of the cartridge, similar studies as for a vial can be performed to optimize and validate component choice as well as assembly parameters and processes. Comparative studies can be performed to choose the most robust cartridge-seal combination given machinability limits. Studies involving multiple crimp configurations, in conjunction with HeLD and RSF, can help elucidate a set of capping parameters that consistently yields an integral seal with low leakage. As with vials, it is possible that dimensional stack-ups, in conjunction with limitations in machinability, yield defects such as loose crimps, misaligned seals, stress cracking from high crimp force, etc. Characterizing these risks through quantitative, deterministic analyses can inform mitigation strategies and quality decision making about the assembly process. With final components and assembly parameters chosen, assembly validation using cartridges capped real-time can be performed, fulfilling best practices outlined through industry standard guidance such as USP <1207>.

Unlike the crimp-sealed end, the barrel end of a cartridge is less a function of an applied force. However, similar optimization and assembly validation practices apply. As with any package system requiring a high degree of leak protection, early on in the development process, the inherent integrity of the chosen product-package system should be evaluated, essentially answering the question: “Are these components, when mated optimally, capable of creating an integral seal?”. This extends to the choice of suitable barrel-plunger interfaces as well. Arguably, since the barrel-plunger interface is not a function of a controllable process such as crimping, inherent integrity evaluations become even more critical. The achieved seal will be primarily a function of the dimensional overlap between the cartridge inner diameter and the plunger outer diameter.

In a laboratory setting, consider a study designed to evaluate barrel-plunger samples paired at dimensional extremes. Within their respective dimensional tolerances, the widest barrel inner diameter paired with the smallest plunger presents the highest risk for leakage, as there may be insufficient or inconsistent compression of the plunger against the cartridge wall. On the other hand, consider the smallest barrel inner diameter paired with the widest plunger. In this case, it is critical to ensure proper function, lack of stress-related defects such as cracking or fitment-related issues risking leakage, such as mis-aligned plungers. A study exploring these dimensional extremes provides confidence that components, within their dimensional stack-up ranges, will provide integral seals. This can be further confirmed by assessing real-world cartridges assembled on the line.

This type of work can be performed at a production facility, using client-owned instrumentation or in-house contract services. Additionally, LDA’s sample filler allows for sample preparation at time of test, enabling analysis of samples previously produced and sealed, or transfer of samples between manufacturing and testing sites. With increasing regulatory scrutiny as well as risk in poor package development and validation practices, helium leak detection, as enabled by the LDA SIMS 1284+ system, is a versatile tool in generating a robust foundation of CCI data for modern package systems

EGG HARBOR TOWNSHIP, N.J. (PRWEB) MAY 22, 2019

Leak Detection Associates (LDA), the world’s premier manufacturer of custom built, helium-based leak testing instruments for the Pharmaceutical, Biotechnology, Medical Device and Food Packaging Industries’ is excited to announce that a formal partnership agreement with Industrial Production Processes (IPP) Ltd has been signed. The agreement will grant exclusive rights for IPP group to represent LDA in the countries of England and Ireland. With locations in Cork, Ireland and Worcestershire, UK, IPP is well positioned in both locations to meet the needs of LDA clients who are in need of helium-based leak testing instruments and systems and the ancillary services that go with them. IPP maintains of staff of 24 service and sales engineers that will be in the ready to serve existing and new clients. As a leading package system instrument and service provider in these geographic areas, IPP has the local knowledge and experience to enhance the already strong Leak Detection Associates’ brand.

“Global expansion is a key initiative of the new Leak Detection Associates management team and we are excited to partner with IPP to make this possible in Ireland and the UK,” commented Brian Mulhall, CEO of Leak Detection Associates. “I have known and worked with Jack Daly and the IPP group in previous settings and the team always brings a high level of knowledge, experience and client care to their work. They are a leading provider of package equipment and laboratory instruments in these countries and we are happy they will be our partners.”

Commented IPP Managing Director Jack Daly, “Partnering with LDA was an easy and natural decision as we are already well established in the relevant packaging instrument field and their technology allows the IPP team to better serve our client base with a broader product and service offering.”

IPP will serve as the exclusive product and service provider for Leak Detections Associates complete line of products and services. The current model SIMS 1284+ helium leak detection instrument is the only custom designed and manufactured helium leak testing instrument that meets the regulatory requirements of the pharma, biotech and medical device industries. In addition, LDA and IPP will offer a full suite of support services that will include custom designed change parts to address various container and package configurations, system parts and add-on options as well as local service, repair and qualification programs.

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EGG HARBOR TOWNSHIP, N.J. (PRWEB) MAY 13, 2019

Leak Detection Associates (LDA), the world’s premier manufacturer of custom built, helium-based leak testing instruments for the Pharmaceutical, Biotechnology, Medical Device and Food Packaging Industries’ is excited to announce the go-live of a completely new Heliumleak.com company website. The redesigned website aims to improve LDA’s ability to communicate directly with the marketplace; serving as a destination to learn LDA’s product and service offerings, news and events, but also as a knowledge center for those interested in helium leak detection applications and CCIT in general.

“For those first exploring any topic, whether it be CCI or unrelated, the first step will be to seek information online.” commented Brian Mulhall, CEO of Leak Detection Associates. “In redesigning LDA’s Heliumleak.com, this was kept in mind. In addition to more detailed descriptions of products, services, and applications of helium to specific package systems, the Resource Center will serve as an industry-leading destination for up-to-date information on all aspects of CCI. Blogs and Whitepapers will routinely be released discussing unique applications of helium leak detection and CCI in general, and an entire section is dedicated to topics such as FDA, EMA, USP, and ASTM guidance.”

The Products section now includes more detail about LDA’s flagship detector, the SIMS 1284+, but also will serve to highlight current and future complimentary offerings, such as LDA’s proprietary vial filling kit and Headspace Analyzing Module (HSAM), which allow for testing of pre-sealed vials. The redesigned services section now clearly highlights LDA’s 20+ years of experience in qualification, calibration, but also consultation, feasibility, and method development services. Uniquely, an entirely new section was added for Applications, which discusses helium-leak approaches for specific package systems, such as vials, pre-filled syringes, combination products, blisters, and more.

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